US8030354B2 - Substituted biphenyl GPR40 modulators - Google Patents

Substituted biphenyl GPR40 modulators

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US8030354B2
US8030354B2 US12/287,036 US28703608A US8030354B2 US 8030354 B2 US8030354 B2 US 8030354B2 US 28703608 A US28703608 A US 28703608A US 8030354 B2 US8030354 B2 US 8030354B2
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alkyl
compound
alkenyl
formula
methyl
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US20090137561A1 (en
Inventor
Sean P. Brown
Qiong Cao
Paul John Dransfield
Xiaohui Du
Zice Fu
Jonathan Houze
Xian Yun Jiao
Yong-Jae Kim
Todd J. Kohn
SuJen Lai
An-Rong Li
Daniel Lin
Jiwen Liu
Jian Luo
Julio C. Medina
Jeffrey D. Reagan
Vatee Pattaropong
Margrit SCHWARZ
Wang Shen
Yongli Su
Gayathri Swaminath
Marc Vimolratana
Yingcai Wang
Yumei Xiong
Li Yang
Ming Yu
Jie Zhang
Liusheng Zhu
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Amgen Inc
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Amgen Inc
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Definitions

  • the present invention relates to compounds capable of modulating the G-protein-coupled receptor GPR40 and/or stimulating GLP-1 secretion, compositions comprising the compounds, and methods for their use for controlling insulin levels in vivo and for the treatment of conditions such as type II diabetes, hypertension, ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels.
  • Insulin imbalances lead to conditions such as type II diabetes mellitus, a serious metabolic disease that afflicts around 5% of the population in Western Societies and over 150 million people worldwide. Insulin is secreted from pancreatic ⁇ cells in response to elevated plasma glucose which is augmented by the presence of fatty acids.
  • G-protein coupled receptor GPR40 The recent recognition of the function of the G-protein coupled receptor GPR40 in modulating insulin secretion has provided insight into regulation of carbohydrate and lipid metabolism in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes, cardiovascular disease and dyslipidemia.
  • GPR40 is a member of the gene superfamily of G-protein coupled receptors (“GPCRs”). GPCRs are membrane proteins characterized as having seven putative transmembrane domains that respond to a variety of molecules by activating intra-cellular signaling pathways critical to a diversity of physiological functions. GPR40 was first identified as an orphan receptor (i.e., a receptor without a known ligand) from a human genomic DNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547. GPR40 is highly expressed in pancreatic ⁇ cells and insulin-secreting cell lines.
  • GPCRs G-protein coupled receptors
  • GPR40 activation is linked to modulation of the G q family of intra-cellular signaling proteins and concomitant induction of elevated calcium levels. It has been recognized that fatty acids serve as ligands for GPR40, and that fatty acids regulate insulin secretion through GPR40. Itoh et al. (2003) Nature 422:173-176; Briscoe et al. (2003) J. Biol. Chem. 278: 11303-11311; Kotarsky et al. (2003) Biochem. Biophys. Res. Commun. 301: 406-410.
  • WO 2004/041266 and EP 1559422 disclose compounds that purportedly act as GPR40 receptor function regulators.
  • WO 2004/106276 and EP 1630152 are directed to condensed ring compounds that purportedly possess GPR40 receptor function modulating action.
  • WO 2005/086661 U.S. Patent Publication No. 2006/0004012, US Patent Publication No. 2006/0270724, and US Patent Publication No. 2007/0066647 disclose compounds useful for modulating insulin levels in subjects and useful for treating type II diabetes.
  • GLP-1 Glucagon-like peptide 1
  • GLP-1 is a peptide that is secreted from the enteroendocrine L-cells of the gut in response to an oral glucose load or food ingestion.
  • the active forms of GLP-1 are processed from a precursor and are denoted GLP-1(7-37) and GLP-1(7-36) amide.
  • GLP-1 has many effects on peripheral tissues.
  • GLP-1 activates its cognate receptor GLP-1R (GLP-1 receptor) on pancreatic beta cells and potentiates glucose stimulated insulin secretion. Additionally, GLP-1 decreases glucagon levels, increases insulin biosynthesis, increases beta cell mass, decreases beta cell apoptosis and inhibits gastric emptying.
  • GLP-1 and GLP-1 mimetics have proven useful in the treatment of type 2 diabetes.
  • GLP-1 has also been found to decrease body weight. Therefore, GLP-1 secretagogues may be useful in treating obesity and preparing medicaments for treating obesity. The decrease in body weight may result from the activities of GLP-1 to inhibit gastric emptying and to increase satiety.
  • the GLP-1 receptor is also expressed in the heart and GLP-1 has been demonstrated to have cardioprotective effects and may be useful in the treatment of cardiovascular disease. The importance of GLP-1 with respect to diabetes, obesity and cardioprotection underscores a need for new therapies and compounds that stimulate GLP-1 secretion.
  • a condition or disorder such as type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema.
  • the present invention provides a compound having the formula I or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof:
  • G is selected from N or CR 11a ;
  • J is selected from N or CR 11b ;
  • L is selected from N or CR 11c ;
  • K is selected from N or CR 11d ;
  • A is selected from —(C 1 -C 12 )alkyl; —(C 2 -C 12 )alkenyl; —(C 1 -C 12 )alkyl-O—(C 1 -C 4 )alkyl; —(C 1 -C 12 )alkyl-OH; —(C 1 -C 12 )alkyl-O—(C 2 -C 4 )alkenyl; —(C 2 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl; —(C 2 -C 12 )alkenyl-OH; —(C 2 -C 12 )alkenyl-O—(C 2 -C 4 )alkenyl; —O—(C 1 -C 12 )alkyl; —O—(C 1 -C 12 )alkenyl; —O—(C 1 -C 12 )alkyl; —O—(C 1
  • X is O, S, or NR a wherein R a is selected from —H or —(C 1 -C 6 )alkyl groups;
  • W, Y, and Z are selected from N or CR 13 ; wherein 0, 1, or 2 of W, Y, and Z is N; and further wherein Z is not N if R 2 is —F;
  • R 1 is selected from —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, heterocyclyl, aryl, or heteroaryl;
  • R 1a is selected from —H and —(C 1 -C 4 )alkyl
  • R 1 and R 1a may join together to form a 3 to 7 membered ring with 0, 1, or 2 heteroatoms selected from O, N, or S;
  • R 2 is selected from —H, —F, —CF 3 , or —O—(C 1 -C 6 )alkyl;
  • R 3 is —H, —F, —Cl, —OH, —(C 1 -C 4 )alkyl, —O—(C 1 -C 3 )alkyl, or —S—(C 1 -C 2 )alkyl;
  • R 7 and R 8 are independently selected from —H and —(C 1 -C 4 )alkyl
  • R 9 and R 10 are independently selected from —H and —(C 1 -C 4 )alkyl
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from —H, —F, —Cl, —(C 1 -C 4 )alkyl, or —O—(C 1 -C 4 )alkyl; and R 11a is absent if G is N; R 11b is absent if J is N, R 11c is absent if L is N; or R 11d is absent if K is N;
  • each of R 12a , R 12b , and R 12c is independently selected from —H, —F, —Cl, —(C 1 -C 4 )alkyl, or —O—(C 1 -C 4 )alkyl;
  • R 13 is selected from —H, —F, —(C 1 -C 4 )alkyl, and —O—(C 1 -C 4 )alkyl; and q is 1 or 2.
  • the invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof, wherein
  • G is selected from N or CR 11a ;
  • J is selected from N or CR 11b ;
  • L is selected from N or CR 11c ;
  • K is selected from N or CR 11d ;
  • A is selected from (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, —O—(C 1 -C 12 )alkyl, —O—(C 2 -C 12 )alkenyl, —O—(C 1 -C 4 )alkyl-aryl, or a heterocycle comprising 4 to 7 ring members of which 1 or 2 are heteroatoms selected from N or O, wherein the heterocycle has 0 or 1 double bond between ring members;
  • X is O or S
  • W, Y, and Z are selected from N or CR 13 ; wherein 0 or 1 of W, Y, and Z is N; and further wherein Z is not N if R 2 is F;
  • R 1 is selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, heterocyclyl, aryl, or heteroaryl;
  • R 1a is selected from H and (C 1 -C 4 )alkyl
  • R 2 is selected from H, F, CF 3 , or (C 1 -C 6 )alkoxy
  • R 3 is H, —OH, —O—(C 1 -C 2 )alkyl, or —S—(C 1 -C 2 )alkyl;
  • R 7 and R 8 are independently selected from H and (C 1 -C 4 )alkyl
  • R 9 and R 10 are independently selected from H and (C 1 -C 4 )alkyl
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from H, F, Cl, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy; and R 11a is absent if G is N; R 11b is absent if J is N, R 11c is absent if L is N; or R 11d is absent if K is N;
  • each of R 12a , R 12b , and R 12c is independently selected from H, F, Cl, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy;
  • R 13 is selected from H, F, (C 1 -C 4 )alkyl, and —O—(C 1 -C 4 )alkyl;
  • q 1 or 2.
  • X is O. In other embodiments, X is S. In still further embodiments X is NR a . In some embodiments X is NR a and R a is selected from H or methyl. In still other embodiments, X is NR a and R a is H.
  • the compound of formula I is a compound of formula II or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula II has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • the compound of formula II is a compound of formula II′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula II′ has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • the compound of formula II is a compound of formula II′′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula II′ has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • W and Z are CH and Y is N such that the compound of formula I has the formula III or is a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula III has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • the compound of formula III is a compound of formula III′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula III′ has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • the compound of formula III is a compound of formula III′′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula III′′ has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • the compound of any of the embodiments is a salt. In other embodiments, the compound of any of the embodiments is a C 1 -C 6 alkyl ester. In some such embodiments, the C 1 -C 6 alkyl ester is a C 1 -C 6 alkyl ester such as a methyl, ethyl, propyl, butyl, isopropyl, pentyl, or hexyl ester. In other such embodiments, the C 1 -C 6 alkyl ester is a methyl, ethyl, propyl, or butyl ester. In some such embodiments, the ester is a methyl or ethyl ester.
  • the compound is a mixture of diastereomers.
  • the percentage of one diastereomer is greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99% based on the total diastereomers present in the mixture.
  • the compound is one specific diastereomer.
  • the compound is a mixture of enantiomers.
  • the mixture comprises both enantiomers where the percent of one enantiomer with respect to both enantiomers is greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%.
  • the compound is a pure single enantiomer.
  • the compound comprises a stereomerically pure S-enantiomer.
  • the compound comprises a stereomerically pure R-enantiomer.
  • the compound comprises a mixture of S- and R-enantiomers.
  • the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent, or excipient, and a compound of any of the embodiments of the invention.
  • the invention provides methods for treating a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.
  • Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the embodiments.
  • the disease or condition is type II diabetes.
  • a compound of any of the embodiments is administered in combination with a second therapeutic agent.
  • the second therapeutic agent is metformin, is a thiazolidinedione, is a DPP-IV inhibitor or is a GLP-1 analog.
  • the second therapeutic agent may be administered before, during, or after administration of the compound of any of the embodiments.
  • the invention provides methods for treating a disease or condition responsive to the modulation of GPR40. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the embodiments.
  • the invention provides methods for treating a disease or condition mediated, regulated, or influenced by pancreatic ⁇ cells. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the embodiments.
  • the invention provides methods for modulating GPR40 function in a cell. Such methods include contacting a cell with a compound of any of the embodiments.
  • the invention provides methods for modulating GPR40 function. Such methods include contacting GPR40 with a compound of any of the embodiments.
  • the invention provides methods for modulating circulating insulin concentration in a subject. Such methods include administering a compound of any of the embodiments to the subject. In some such embodiments, the circulating insulin concentration is increased in the subject after administration whereas in other such embodiments, the circulating insulin concentration is decreased in the subject after administration.
  • the invention provides the use of a compound of any of the embodiments for treating a disease or condition or for preparing a medicament for treating a disease or condition where the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.
  • the disease or condition is type II diabetes.
  • the compounds of the invention may also be used to prepare medicaments that include a second therapeutic agent such as metformin, a thiazolidinedione, or a DPP-IV inhibitor.
  • the invention provides the use of a compound of any of the embodiments for modulating GPR40 or for use in the preparation of a medicament for modulating GPR40.
  • the invention provides a therapeutic composition that includes a compound of any of the embodiments and a second therapeutic agent such as those described herein, for example, metformin a thiazolidinedione, or a DPP-IV inhibitor, as a combined preparation for simultaneous, separate, or sequential use in the treatment of a disease or condition mediated by GPR40.
  • a disease or condition is type II diabetes.
  • the compound of any of the embodiments and the second therapeutic agent are provided as a single composition, whereas in other embodiments they are provided separately as parts of a kit.
  • the invention provides a compound of any of the embodiments described herein for use as a medicament.
  • the invention provides a compound of any of the embodiments described herein for use in modulating GPR40.
  • the invention provides a compound of any of the embodiments described herein for use in a method for treating a disease or condition selected from type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, or edema.
  • a disease or condition selected from type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis,
  • the compounds of the invention have been found to stimulate GLP-secretion.
  • Cells contacted with compounds of the invention have been found to increase GLP-1 secretion. Therefore, in some embodiments, the invention provides a method of stimulating GLP-1 secretion by cells. Such methods typically include contacting a cell capable of producing GLP-1 with a compound of any of the embodiments set forth herein.
  • Administration of the compounds of the invention to subjects has also been found to provide increased levels of GLP-1 in the blood plasma of such subjects. Therefore, in some embodiments, a compound of any of the embodiments described herein may be used to stimulate GLP-1 secretion and increase the blood plasma level of GLP-1 in a subject.
  • the compounds of the invention both stimulate GLP-1 secretion and activate GPR40. Therefore, in some embodiments, the compounds of the invention both stimulate GLP-1 secretion and display incretin effect by activating GPR40.
  • the invention further provides a method for increasing GLP-1 levels in the blood plasma of a subject.
  • Such methods typically include administering a compound of any of the embodiments to a subject.
  • the subject is a diabetic patient.
  • the subject is an obese patient.
  • the invention provides a method for stimulating weight loss in a subject.
  • a compound of any of the embodiments is administered to a subject in an effective amount to stimulate weight loss in the subject.
  • the compounds of the invention may be administered in the fasted or non-fasted state. Therefore, in some embodiments, a compound of any of the embodiments is administered to a subject prior to a meal.
  • the compound is administered 2 hours, 1, hour, 30 minutes, or 15 minutes before a meal.
  • a compound of any embodiments set forth herein is administered to a subject during a meal.
  • a compound of any of the embodiments described herein is administered to a subject within 2 hours, within 1 hour, within 30 minutes, or within 15 minutes of a meal.
  • the invention provide a process for hydrogenating a compound of formula V, the method comprising: (a) reacting a compound of formula V with H 2 in the presence of a transition metal or a transition metal complex to form a compound of formula VIA, a compound of formula VIB or mixture of the compound of formula VIA and the compound of formula VIB.
  • the compounds of formula V, VIA, and VIB have the following structures:
  • the invention provides a compound of formula V, VIA, and/or VIB.
  • the variables have the definitions provided herein with respect to the process for hydrogenating a compound of formula V.
  • the variables have any of the definitions provided with respect to any of the embodiments of the process for hydrogenating a compound of formula V.
  • R 14 is OH.
  • R 15 and R 16 are both methyl groups.
  • the transition metal or transition metal complex comprises palladium, platinum, nickel, or rhodium.
  • the reduction may be accomplished using palladium on carbon, Raney nickel, PtO 2 or various rhodium compounds.
  • the transition metal or transition metal complex is palladium, and in some such embodiments is palladium on carbon.
  • Various supported catalysts known to those skilled in the art may be used in conjunction with this process.
  • the process is an enantioselective process.
  • the method includes reacting a compound of formula V with H 2 in the presence of a transition metal or a transition metal complex and a phosphine ligand to form a compound of formula VIA, a compound of formula VIB, or a mixture of the compound of formula VIA and the compound of formula VIB.
  • the phosphine ligand comprises at least one chiral center.
  • R 14 is —OH.
  • R 15 and R 16 are both —CH 3 .
  • n 1
  • R 12b and R 12c are both —H.
  • R 12a is H or halo.
  • R 12a is H whereas in other embodiments, R 12a is F.
  • the transition metal or the transition metal complex comprises rhodium.
  • the transition metal complex is generated from Rh(COD) 2 BF 4 , Rh(COD) 2 SbF 6 , or Rh(NBD) 2 BF 4 where COD represents the 1,5-cyclooctadiene ligand and NBD represents the norbornadiene ligand.
  • the phosphine is a diphosphine.
  • the diphosphine comprises a ferrocene group.
  • the diphosphine is selected from
  • the diphosphine is an enantiomer of one of the compounds shown above.
  • the compound of formula V is reacted with H 2 at a pressure of from 15 to 1400 psi. In some such embodiments, the pressure ranges from 50 to 400 psi.
  • the compound of formula V is reacted with H 2 in a mixture comprising at least one solvent selected from an ethereal solvent, an ester solvent, an aromatic solvent, a halogenated hydrocarbon solvent, a ketone solvent, or a C 1 -C 4 alcohol solvent.
  • the at least one solvent comprises an ethereal solvent selected from tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydropyran, diethylether, dipropylether, or dibutylether.
  • the at least one solvent comprises tetrahydrofuran. In other such embodiments, the at least one solvent comprises at least one of tetrahydrofuran, toluene, acetone, methyl ethyl ketone, ethanol, or methanol.
  • the transition metal complex is mixed with the phosphine in a solvent prior to adding the compounds of formula V.
  • the solvent is an ethereal solvent such as tetrahydrofuran
  • the transition metal complex is selected from Rh(COD) 2 BF 4 , Rh(COD) 2 SbF 6 , or Rh(NBD) 2 BF 4 .
  • the phosphine is a diphosphine comprising a ferrocenyl group such as one of those described herein.
  • the compound of formula I is reacted with H 2 at a temperature ranging from 15° C. to 60° C. In some such embodiments, the temperature ranges from 20° C. to 45° C.
  • the enantiomeric excess of one of the products is greater than 50%, greater than 60%, greater than 75%, greater than 85%, greater than 90%, greater than 95%, or greater than 98%.
  • the conversion of the compound of formula V to the compound of formula VIA, the compound of formula VIB, or the mixture of the compound of formula VIA and the compound of formula VIB is greater than 50%, greater than 70%, greater than 80%, or greater than 95%.
  • FIG. 1 is a graph showing displacement of 3 H-labeled Comparative Compound 1 by various unlabeled compounds, including Examples 9 and 14. Unlabeled Comparative Compound 1 displaced the 3 H-labeled Comparative Compound. In direct contrast, Examples 9 and 14 enhanced the total binding of 3 H-labeled Comparative Compound 1. These results indicate that Examples 9 and 14 interact with the GPR40 receptor in a manner that is different from Comparative Compound 1.
  • FIG. 2 is a graph showing Aequorin luminescence in response to various compounds as a function of concentration. This graph shows that Examples 14 and 66.4 have activity which is equivalent to naturally occurring fatty acid ligands such as ⁇ -linolenic acid and docosahexaenoic acid.
  • FIG. 3 is a graph showing inositol phosphate accumulation in response to various compounds as a function of concentration. This graph shows that Examples 9 and 14 have activity which is greater than Comparative Compound 1.
  • FIG. 4 is a graph showing insulin secretion from C57/B16 mouse islets as a function of concentration of Examples 9 and 14.
  • FIG. 5 is a graph showing the concentration of GLP-1 secreted into culture medium as a function of the amount of Example compounds 14 and 69.8.
  • the GLP-1 was secreted from fetal rat intestinal cells isolated from E19 rat embryos. The cultured cells were treated with serial dilutions of the indicated compounds, and GLP-1 secreted into the culture medium was determined. These results indicate that these compounds significantly stimulated GLP-1 secretion.
  • FIG. 6 is a graph showing the concentration of GLP-1 secreted into culture medium as a function of the amount of Example compound 66.6.
  • the GLP-1 was secreted from fetal rat intestinal cells isolated from E19 rat embryos. The cultured cells were treated with serial dilutions of the indicated compound, and GLP-1 secreted into the culture medium was determined. These results indicate that this compound significantly stimulated GLP-1 secretion.
  • FIG. 7 is a graph showing the concentration of GLP-1 secreted into culture medium as a function of the amount of Example compounds 14, 66.17, 77.3, and 83.1.
  • the GLP-1 was secreted from fetal rat intestinal cells isolated from E19 rat embryos. The cultured cells were treated with serial dilutions of the indicated compounds, and GLP-1 secreted into the culture medium was determined. These results indicate that these compounds significantly stimulated GLP-1 secretion.
  • FIG. 8 is a graph showing GLP-1 plasma levels in C57BL6 mice under overnight fast condition after administration of vehicle and Example 14 (100 mg/kg). Each group had 12 mice. The * symbol indicates that for this point p ⁇ 0.05 (student's t-test) when treatment with example compound is compared with vehicle control. Only the top part of the error bars is shown.
  • FIG. 9 is a graph showing GLP-1 plasma levels in C57BL6 mice under non-fasted condition after administration of vehicle and Example 14 (100 mg/kg). Each group had 12 mice. The * symbol indicates that for this point p ⁇ 0.05 (student's t-test) when treatment with example compound is compared with vehicle control. Only the top part of the error bars is shown.
  • FIG. 10 is a graph showing GLP-1 plasma levels in HF/STZ mice under non-fasted condition after administration of vehicle and Example 14 (100 mg/kg). Each group had 12 mice. The * symbol indicates that for this point p ⁇ 0.05 (student's t-test) when treatment with example compound is compared with vehicle control. Only the top part of the error bars is shown.
  • FIG. 11 is a graph showing GLP-1 plasma levels in HF/STZ mice under non-fasted condition after administration of vehicle and Example 83.1 (30 mg/kg). Each group had 12 mice. The * symbol indicates that for this point p ⁇ 0.05 (student's t-test) when treatment with example compound is compared with vehicle control. Only the top part of the error bars is shown.
  • treat are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms. In some instances treating may also involve prevention of symptoms.
  • prevention refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a subject from acquiring a condition or disease, or reducing a subject's risk of acquiring a condition or disease.
  • therapeutically effective amount refers to that amount of the compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought.
  • therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated in a subject.
  • the therapeutically effective amount in a subject will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • subject is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • Inhibitors are compounds that, for example, bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction, such as, for instance, antagonists.
  • Activators are compounds that, for example, bind to, stimulate, increase, activate, facilitate, enhance activation, sensitize or up regulate signal transduction, such as agonists for instance. Modulation may occur in vitro or in vivo.
  • GPR40-mediated condition or disorder refers to a condition or disorder characterized by inappropriate, for example, less than or greater than normal, GPR40 activity.
  • a GPR40-mediated condition or disorder may be completely or partially mediated by inappropriate GPR40 activity.
  • a GPR40-mediated condition or disorder is one in which modulation of GPR40 results in some effect on the underlying condition or disease (e.g., a GPR40 modulator results in some improvement in patient well-being in at least some patients).
  • Exemplary GPR40-mediated conditions and disorders include cancer and metabolic disorders, e.g., diabetes, type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, thrombotic disorders, metabolic syndrome, syndrome X and related disorders, e.g., cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, and edema.
  • cancer and metabolic disorders e.g., diabetes, type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, thrombotic disorders, metabolic
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (e.g., C 1 -C 10 means one to ten carbons).
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, cyclohexyl, (cyclohexyl)methyl, methylcyclohexyl, dimethylcyclohexyl, cyclopropyl, cyclopropylmethyl, methylcyclopropyl, cyclobutyl, cyclobutylmethyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclopentylmethyl, dimethylcyclopentyl, and homologs and isomers thereof, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be substituted or unsubstituted.
  • alkenyl by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2 -C 8 means two to eight carbons) and one or more double bonds.
  • alkenyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), cyclopentenyl, cyclohexenyl, 5,5-dimethylcycopentenyl, 6,6-dimethylcyclohexenyl, cycloheptenyl, cycloheptadienyl, and higher homologs and isomers thereof.
  • alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2 -C 8 means two to eight carbons) and one or more triple bonds.
  • alkynyl groups include, but are not limited to, ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers thereof.
  • alkoxy refers to a group of formula —O-alkyl where alkyl has the definition provided above.
  • An alkoxy group can have a specified number of carbon atoms.
  • a methoxy group (—OCH 3 ) is a C 1 alkoxy group.
  • Alkoxy groups typically have from 1 to 10 carbon atoms. Examples of alkoxy group include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, and the like.
  • cycloalkyl by itself, or in combination with other terms, represents, unless otherwise stated, a cyclic type of “alkyl” in which 3 or more carbon atoms form a ring.
  • cycloalkyl is meant to be included in the term “alkyl”.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Cycloalkyl groups typically include from 3 to 14 or 3 to 10 ring members. Cycloalkyl groups may be monocyclic, bicyclic, or multicyclic. Therefore, in addition to the groups described above, cycloalkyl groups include norbornyl and adamantyl groups.
  • cycloalkenyl by itself, or in combination with other terms, represents, unless otherwise stated, a cyclic type of “alkenyl” in which 3 or more carbon atoms form a ring that includes at least one carbon-carbon double bond.
  • cycloalkenyl is meant to be included in the term “alkenyl”.
  • Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • Cycloalkenyl groups typically include from 3 to 14 or 3 to 10 ring members. Cycloalkenyl groups may be monocyclic, bicyclic, or multicyclic.
  • heterocyclyl by itself or in combination with other terms, represents, unless otherwise stated, a ring system in which one ore more ring members is a heteroatom selected from N, O, or S.
  • the heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • a heterocyclyl group can also be attached to the remainder of the molecule through a carbon atom of the ring.
  • Heterocyclyl groups typically include from 3 to 10 ring members of which 1, 2, or 3 are heteroatoms.
  • Heterocyclyl groups can be saturated or may include some unsaturation.
  • Heterocyclyl groups may also be substituted or unsubstituted.
  • heterocyclyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, 4,5-dihydroisoxazol-3-yl, and the like.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at any position of the heteroalkyl group.
  • Examples include —CH 2 —CH 2 —O—CH 3 , —CH 2 —CH 2 —NH—CH 3 , —CH 2 —CH 2 —N(CH 3 )—CH 3 , —CH 2 —S—CH 2 —CH 3 , —CH 2 —CH 2 —S(O)—CH 3 , —CH 2 —CH 2 —S(O) 2 —CH 3 , and —CH 2 —CH ⁇ N—OCH 3 .
  • Up to two heteroatoms may be consecutive, such as, for example, —CH 2 —NH—OCH 3 .
  • a prefix such as (C 2 -C 8 ) is used to refer to a heteroalkyl group
  • the number of carbons (2 to 8, in this example) is meant to include the heteroatoms as well.
  • a C 2 -heteroalkyl group is meant to include, for example, —CH 2 OH (one carbon atom and one heteroatom replacing a carbon atom) and —CH 2 SH.
  • a heteroalkyl group is a oxyalkyl group.
  • (C 2 -C 5 )oxyalkyl is meant to include, for example —CH 2 —O—CH 3 (a C 3 -oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), —CH 2 CH 2 CH 2 CH 2 OH, and the like.
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • halo(C 1 -C 4 )alkyl is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m′+1) halogen atoms).
  • perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m′+1) halogen atoms, where m′ is the total number of carbon atoms in the alkyl group.
  • perhalo(C 1 -C 4 )alkyl is meant to include trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatom ring members selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Heteroaryl groups can be unsubstituted or substituted. In some embodiments, a heteroaryl group includes 1 or 2 heteroatoms.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom of the ring.
  • aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, dibenzofuryl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
  • an aryl group refers to an aromatic group that includes from 6-10 ring members such that it is a (C 6 -C 10 )aryl group.
  • heteroaryl groups include 5 to 10 ring members of which 1 or 2 is selected from O, N, or S.
  • aryl refers to a phenyl or naphthyl group which is unsubstituted or substituted.
  • heteroaryl refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, furyl, thienyl (thiophenyl), pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, triazolyl, tetrazolyl, quinoxalinyl, or quinolyl group which is unsubstituted or substituted.
  • aryl when used in combination with other terms (e.g., aryloxy, arylalkoxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
  • an alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like.
  • aryl(C 1 -C 4 )alkoxy is mean to include radicals in which an aryl group is attached to an alkyl group having 1 to 4 carbon atoms that is bonded to an O which is attached to the rest of the molecule. Examples include substituted and unsubstituted phenylmethoxy, phenylethoxy, phenylpropoxy, pyridylmethoxy, and the like.
  • Substituents for the alkyl radicals can be a variety of groups selected from: —OR′, ⁇ O, ⁇ NR′, ⁇ N—OR′, —NR′R′′, R′, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′—C(O)NR′′R′′′, —NR′—SO 2 NR′′R′′′, —NR′′CO 2 R′, —NH—C(NH 2 ) ⁇ NH, —NR′C(NH 2 ) ⁇ NH, —NH—C(NH 2 ) ⁇ NR′, —SiR′R′′R′′′, —S(O)R′, —SO
  • R′, R′′ and R′′′ each independently refer to hydrogen; unsubstituted (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, and heteroalkyl; unsubstituted aryl; unsubstituted heterocyclyl; heterocyclyl substituted with up to three unsubstituted (C 1 -C 2 )alkyl groups; aryl substituted with one to three halogens, unsubstituted (C 1 -C 2 )alkyl, —O—(C 1 -C 4 )alkyl, and —S—(C 1 -C 4 )alkyl groups; unsubstituted halo(C 1 -C 4 )alkyl; unsubstituted —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl; unsubstituted —(C 1 -C 4 )alkyl-ary
  • R′ and R′′ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.
  • —NR′R′′ is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • an alkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an alkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups such as trihaloalkyl (e.g., —CF 3 and —CH 2 CF 3 ).
  • Preferred substituents for the alkyl radicals are selected from: —OR′, ⁇ O, —NR′R′′, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′′CO 2 R′, —NR′—SO 2 NR′′R′′′, —S(O)R′, —SO 2 R′, —SO 2 NR′R′′, —NR′′SO 2 R, —CN, —(C 2 -C 5 )alkynyl, —(C 2 -C 5 )alkenyl, R′, and —NO 2 , where R′ and R′′ are as defined above.
  • substituents are selected from: —OR′, ⁇ O, —NR′R′′, halogen, —OC(O)R′, —CO 2 R′, —CONR′R′′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′′CO 2 R′, —NR′—SO 2 NR′′R′′′, —SO 2 R′, —SO 2 NR′R′′, —NR′′SO 2 R, —CN, —(C 2 -C 5 )alkynyl, —(C 2 -C 5 )alkenyl, and —NO 2 .
  • substituents for the aryl and heteroaryl groups are varied and are selected from: -halogen, —OR′, —OC(O)R′, —NR′R′′, —SR′, —R′, —CN, —NO 2 , —CO 2 R′, —CONR′R′′, —C(O)R′, —OC(O)NR′R′′, —NR′′C(O)R′, —NR′′C(O) 2 R′, —NR′—C(O)NR′′R′′′, —NH—C(NH 2 ) ⁇ NH, —NR′C(NH 2 ) ⁇ NH, —NH—C(NH 2 ) ⁇ NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R′′, —N 3 , —CH(Ph) 2 , perfluoro(C 1 -C 4 )alkoxy, and perfluoro(C 1 -
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)—(CH 2 ) q —U—, wherein T and U are independently —NH—, —O—, —CH 2 —, or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r —B—, wherein A and B are independently —CH 2 —, —O—, —NH—, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 NR′—, or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CH 2 ) s —X—(CH 2 ) t —, where s and t are independently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O) 2 —, or —S(O) 2 NR′—.
  • the substituent R′ in —NR′— and —S(O) 2 NR′— is selected from hydrogen or unsubstituted (C 1 -C 6 )alkyl. Otherwise, R′ is as defined above.
  • heteroatom is meant to include oxygen (O), nitrogen (N), and sulfur (S).
  • pharmaceutically acceptable salt is meant to include a salt of the active compound which is prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compound described herein.
  • a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
  • salts of amino acids such as arginine and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al. (1977) J. Pharm. Sci. 66:1-19).
  • Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
  • the invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • solvate refers to a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • the compounds, salts of the compounds, tautomers of the compound, and salts of the tautomers may include a solvent or water such that the compound or salt is a solvate or hydrate.
  • certain compounds of the invention may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that convenience, referral to a compound of a given structural formula includes tautomers of the structure represented by the structural formula.
  • Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. Furthermore, atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or heteroaromatic rings bonded to one another are intended to be encompassed within the scope of the invention.
  • stereoisomer or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • a bond drawn with a wavy line indicates that both stereoisomers are encompassed.
  • Various compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds.
  • This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms.
  • mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention.
  • These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.
  • the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., GPR40 assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. For example, if a variable is said to be H, this means that variable may also be deuterium (D) or tritium (T).
  • a class of compounds that modulates GPR40 is described herein. Depending on the biological environment (e.g., cell type, pathological condition of the subject, etc.), these compounds can modulate, e.g., activate or inhibit, the actions of GPR40.
  • the compounds By modulating GPR40, the compounds find use as therapeutic agents capable of regulating insulin levels in a subject.
  • the compounds find use as therapeutic agents for modulating diseases and conditions responsive to modulation of GPR40 and/or mediated by GPR40 and/or mediated by pancreatic ⁇ cells.
  • diseases and conditions include diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, cancer, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, nephropathy, thrombotic disorders, diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia and edema. Additionally, the compounds are useful for the treatment and/or prevention of complications of these diseases and disorders (e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth).
  • complications of these diseases and disorders e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth.
  • the present invention provides a compound having the formula I or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof:
  • G is selected from N or CR 11a ;
  • J is selected from N or CR 11b ;
  • L is selected from N or CR 11c ;
  • K is selected from N or CR 11d ;
  • A is selected from —(C 1 -C 12 )alkyl; —(C 2 -C 12 )alkenyl; —(C 1 -C 12 )alkyl-O—(C 1 -C 4 )alkyl; —(C 1 -C 12 )alkyl-OH; —(C 1 -C 12 )alkyl-O—(C 2 -C 4 )alkenyl; —(C 2 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl; —(C 2 -C 12 )alkenyl-OH; —(C 2 -C 12 )alkenyl-O—(C 2 -C 4 )alkenyl; —O—(C 1 -C 12 )alkyl; —O—(C 1 -C 12 )alkenyl; —O—(C 1 -C 12 )alkyl; —O—(C 1
  • X is O, S, or NR a wherein R a is selected from —H or —(C 1 -C 6 )alkyl groups;
  • W, Y, and Z are selected from N or CR 13 ; wherein 0, 1, or 2 of W, Y, and Z is N; and further wherein Z is not N if R 2 is —F;
  • R 1 is selected from —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, heterocyclyl, aryl, or heteroaryl;
  • R 1a is selected from —H and —(C 1 -C 4 )alkyl
  • R 1 and R 1a may join together to form a 3 to 7 membered ring with 0, 1, or 2 heteroatoms selected from O, N, or S;
  • R 2 is selected from —H, —F, —CF 3 , or —O—(C 1 -C 6 )alkyl;
  • R 3 is —H, —F, —Cl, —OH, —(C 1 -C 4 )alkyl, —O—(C 1 -C 3 )alkyl, or —S—(C 1 -C 2 )alkyl;
  • R 7 and R 8 are independently selected from —H and —(C 1 -C 4 )alkyl
  • R 9 and R 10 are independently selected from —H and —(C 1 -C 4 )alkyl
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from —H, —F, —Cl, —(C 1 -C 4 )alkyl, or —O—(C 1 -C 4 )alkyl; and R 11a is absent if G is N; R 11b is absent if J is N, R 11c is absent if L is N; or R 11d is absent if K is N;
  • each of R 12a , R 12b , and R 12c is independently selected from —H, —F, —Cl, —(C 1 -C 4 )alkyl, or —O—(C 1 -C 4 )alkyl;
  • R 13 is selected from —H, —F, —(C 1 -C 4 )alkyl, and —O—(C 1 -C 4 )alkyl; and q is 1 or 2.
  • the invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof, wherein
  • G is selected from N or CR 11a ;
  • J is selected from N or CR 11b ;
  • L is selected from N or CR 11c ;
  • K is selected from N or CR 11d ;
  • A is selected from (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, —O—(C 1 -C 12 )alkyl, —O—(C 2 -C 12 )alkenyl, —O—(C 1 -C 4 )alkyl-aryl, or a heterocycle comprising 4 to 7 ring members of which 1 or 2 are heteroatoms selected from N or O, wherein the heterocycle has 0 or 1 double bond between ring members;
  • X is O, S, or NR a wherein R a is selected from H or (C 1 -C 6 )alkyl groups;
  • W, Y, and Z are selected from N or CR 13 ; wherein 0 or 1 of W, Y, and Z is N; and further wherein Z is not N if R 2 is F;
  • R 1 is selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, heterocyclyl, aryl, or heteroaryl;
  • R 1a is selected from H and (C 1 -C 4 )alkyl
  • R 2 is selected from H, F, CF 3 , or (C 1 -C 6 )alkoxy
  • R 3 is H, —OH, —O(C 1 -C 2 )alkyl, or —S(C 1 -C 2 )alkyl;
  • R 7 and R 8 are independently selected from H and (C 1 -C 4 )alkyl
  • R 9 and R 10 are independently selected from H and (C 1 -C 4 )alkyl
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from H, F, Cl, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy; and R 11a is absent if G is N; R 11b is absent if J is N, R 11c is absent if L is N; or R 11d is absent if K is N;
  • each of R 12a , R 12b , and R 12c is independently selected from H, F, Cl, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy;
  • R 13 is selected from H, F, (C 1 -C 4 )alkyl, and —O—(C 1 -C 4 )alkyl; and q is 1 or 2.
  • the invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof, wherein
  • G is selected from N or CR 11a ;
  • J is selected from N or CR 11b ;
  • L is selected from N or CR 11c ;
  • K is selected from N or CR 11d ;
  • A is selected from (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, —O—(C 1 -C 12 )alkyl, —O—(C 2 -C 12 )alkenyl, —O—(C 1 -C 4 )alkyl-aryl, or a heterocycle comprising 4 to 7 ring members of which 1 or 2 are heteroatoms selected from N or O, wherein the heterocycle has 0 or 1 double bond between ring members;
  • X is O or S
  • W, Y, and Z are selected from N or CR 13 ; wherein 0 or 1 of W, Y, and Z is N; and further wherein Z is not N if R 2 is F;
  • R 1 is selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, heterocyclyl, aryl, or heteroaryl;
  • R 1a is selected from H and (C 1 -C 4 )alkyl
  • R 2 is selected from H, F, CF 3 , or (C 1 -C 6 )alkoxy
  • R 3 is H, —OH, —O—(C 1 -C 2 )alkyl, or —S—(C 1 -C 2 )alkyl;
  • R 7 and R 8 are independently selected from H and (C 1 -C 4 )alkyl
  • R 9 and R 10 are independently selected from H and (C 1 -C 4 )alkyl
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from H, F, Cl, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy; and R 11a is absent if G is N; R 11b is absent if J is N, R 11c is absent if L is N; or R 11d is absent if K is N;
  • each of R 12a , R 12b , and R 12c is independently selected from H, F, Cl, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy;
  • R 13 is selected from H, F, (C 1 -C 4 )alkyl, and —O—(C 1 -C 4 )alkyl;
  • q 1 or 2.
  • X is O, S, or NR a wherein R a is selected from H or unsubstituted (C 1 -C 6 )alkyl groups;
  • R 1 is selected from H, unsubstituted —(C 1 -C 6 )alkyl, unsubstituted —(C 2 -C 6 )alkenyl, unsubstituted —(C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, heterocyclyl, aryl, heteroaryl, —(C 1 -C 6 )alkyl substituted with from 1 to 3 substituents selected from —F or —OH, or —(C 2 -C 6 )alkenyl substituted with from 1 to 3 substituents selected from —F or —OH;
  • R 1a is selected from H, unsubstituted —(C 1 -C 4 )alkyl, or —(C 1 -C 4 )alkyl substituted with from 1 to 3 substituents selected from F and OH;
  • R 1 and R 1a may join together to form a 3 to 7 membered ring with 0, 1, or 2 heteroatoms selected from O, N, or S;
  • R 2 is selected from —H, —F, —CF 3 , or —O—(C 1 -C 6 )alkyl;
  • R 3 is —H, —F, —Cl, —OH, —S(C 1 -C 2 )alkyl, unsubstituted —(C 1 -C 4 )alkyl, unsubstituted —O(C 1 -C 3 )alkyl, —(C 1 -C 4 )alkyl substituted with from 1 to 3 substituents selected from —F, —OH, ( ⁇ O), or —O(C 1 -C 2 )alkyl, or substituted —O(C 1 -C 3 )alkyl, wherein the alkyl group of the substituted —O(C 1 -C 3 )alkyl is substituted with from 1 to 3 substituents selected from —F, —OH, or —O(C 1 -C 2 )alkyl;
  • R 7 and R 8 are independently selected from H and unsubstituted —(C 1 -C 4 )alkyl
  • R 9 and R 10 are independently selected from H and unsubstituted —(C 1 -C 4 )alkyl
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from —H, —F, —Cl, —(C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, or —CF 3 ; and R 11a is absent if G is N; R 11b is absent if J is N, R 11c is absent if L is N; or R 11d is absent if K is N;
  • each of R 12a , R 12b , and R 12c is independently selected from —H, —F, —Cl, unsubstituted —(C 1 -C 4 )alkyl, CF 3 , or —O(C 1 -C 4 )alkyl; and
  • R 13 is selected from —H, —F, —(C 1 -C 4 )alkyl, and —O—(C 1 -C 4 )alkyl. In some such embodiments, q is 1.
  • R 1 is selected from H, unsubstituted —(C 1 -C 6 )alkyl, unsubstituted —(C 2 -C 6 )alkenyl, unsubstituted —(C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, heterocyclyl, aryl, heteroaryl, —(C 1 -C 6 )alkyl substituted with from 1 to 3 substituents selected from —F or —OH, or —(C 2 -C 6 )alkenyl substituted with from 1 to 3 substituents selected from —F or —OH.
  • R 1a is selected from H, unsubstituted —(C 1 -C 4 )alkyl, or —(C 1 -C 4 )alkyl substituted with from 1 to 3 substituents selected from F and OH; or R 1 and R 1a may join together to form a 3 to 7 membered ring with 0, 1, or 2 heteroatoms selected from O, N, or S.
  • R 3 is —H, —F, —Cl, —OH, —S(C 1 -C 2 )alkyl, unsubstituted —(C 1 -C 4 )alkyl, unsubstituted —O(C 1 -C 3 )alkyl, —(C 1 -C 4 )alkyl substituted with from 1 to 3 substituents selected from —F, —OH, ( ⁇ O), or —O(C 1 -C 2 )alkyl, or substituted —O(C 1 -C 3 )alkyl, wherein the alkyl group of the substituted —O(C 1 -C 3 )alkyl is substituted with from 1 to 3 substituents selected from —F, —OH, or —O(C 1 -C 2 )alkyl.
  • R 7 and R 8 are independently selected from H and unsubstituted —(C 1 -C 4 )alkyl.
  • R 9 and R 10 are independently selected from H and unsubstituted —(C 1 -C 4 )alkyl.
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from —H, —F, —Cl, —(C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl, or —CF 3 ; and R 11a is absent if G is N; R 11b is absent if J is N, R 11c is absent if L is N; or R 11d is absent if K is N.
  • each of R 12a , R 12b , and R 12c is independently selected from —H, —F, —Cl, unsubstituted —(C 1 -C 4 )alkyl, CF 3 , or —O(C 1 -C 4 )alkyl.
  • R 13 is selected from —H, —F, —(C 1 -C 4 )alkyl, and —O—(C 1 -C 4 )alkyl.
  • A is selected from —(C 4 -C 12 )alkyl, —(C 4 -C 12 )alkenyl, —(C 3 -C 12 )alkyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkyl-OH, —(C 3 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkenyl-OH, —O—(C 4 -C 12 )alkyl, —O—(C 4 -C 12 )alkenyl, a heterocycle comprising 4 to 7 ring members of which 1 or 2 are heteroatoms selected from N or O, wherein the heterocycle has 0 or 1 double bond between ring members and is unsubstituted or is substituted with from 1 to 4 (C 1 -C 2 )alkyl groups, a —(C 1 -C
  • A is selected from —(C 4 -C 12 )alkyl, —(C 4 -C 12 )alkenyl, —(C 3 -C 12 )alkyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkyl-OH, —(C 3 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkenyl-OH, —O—(C 4 -C 12 )alkyl, or —O—(C 4 -C 12 )alkenyl, wherein the alkyl and alkenyl groups of —(C 4 -C 12 )alkyl, —(C 4 -C 12 )alkenyl, —(C 3 -C 12 )alkyl-O—(C 1 -C 4 )alkyl, —(C 3 -C
  • A is selected from —(C 4 -C 12 )alkyl, —(C 4 -C 12 )alkenyl, —(C 3 -C 12 )alkyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkyl-OH, —(C 3 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkenyl-OH, wherein the alkyl and alkenyl groups of —(C 4 -C 12 )alkyl, —(C 4 -C 12 )alkenyl, —(C 3 -C 12 )alkyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkyl-O—H, —(C 3 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl
  • A is selected from —(C 4 -C 12 )alkyl, —(C 4 -C 12 )alkenyl, —(C 3 -C 12 )alkyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkyl-OH, —(C 3 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkenyl-OH, wherein the alkyl and alkenyl groups of —(C 4 -C 12 )alkyl, —(C 4 -C 12 )alkenyl, —(C 3 -C 12 )alkyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkyl-O—H, —(C 3 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl
  • A is a 5 to 7 membered cycloalkyl or cycloalkenyl group comprising from 1 to 4 methyl groups.
  • A is a —(C 3 -C 12 )alkyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkyl-OH, —(C 3 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl, or —(C 3 -C 12 )alkenyl-OH.
  • each of the alkyl and alkenyl groups of the —(C 3 -C 12 )alkyl-O—(C 1 -C 4 )alkyl, —(C 3 -C 12 )alkyl-OH, —(C 3 -C 12 )alkenyl-O—(C 1 -C 4 )alkyl, or —(C 3 -C 12 )alkenyl-OH are unsubstituted whereas in other embodiments, each is substituted with 1 to 4 substituents selected from —OH, unsubstituted —O—(C 1 -C 2 )alkyl, or unsubstituted —(C 1 -C 2 )alkyl.
  • A is a —(C 4 -C 8 )alkyl-O—(C 1 -C 2 )alkyl, —(C 4 -C 8 )alkyl-OH, —(C 4 -C 8 )alkenyl-O—(C 1 -C 2 )alkyl, or —(C 4 -C 8 )alkenyl-OH and each of the alkyl and alkenyl groups of —(C 4 -C 8 )alkyl-O—(C 1 -C 2 )alkyl, —(C 4 -C 8 )alkyl-OH, —(C 4 -C 8 )alkenyl-O—(C 1 -C 2 )alkyl, or —(C 4 -C 8 )alkenyl-OH are unsubstituted or are substituted with 1 substituent selected from —OH, unsubstituted —O—(C 1 -C 2 )
  • X is O. In other embodiments, X is S. In still further embodiments X is NR a . In some embodiments X is NR a and R a is selected from H or methyl. In still other embodiments, X is NR a and R a is H.
  • the compound of formula I is a compound of formula I′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof,
  • the compound of formula I is a compound of formula I′′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof:
  • G is CR 11a ; J is CR 11b ; L is CR 11c ; and K is CR 11d .
  • each of R 11a , R 11b , R 11c , and R 11d is H.
  • each of R 12a , R 12b , and R 12c is H.
  • R 12a and R 12b are H and R 12c is F.
  • R 12b and R 12c are H and R 12a is F.
  • R 12a and R 12c are H and R 12b is F.
  • R 11a is F and each of R 11b , R 11c , and R 11d is H.
  • R 11b is F and each of R 11a , R 11c , and R 11d is H.
  • R 11c is F and each of R 11a , R 11b , and R 11d is H.
  • R 11d is F and each of R 11a , R 11b , and R 11c is H.
  • R 11a , R 11b , R 11c , and R 11d is H or where R 11a is F and each of R 11b , R 11c , and R 11d is H, R 12c is F, R 12a is H, and R 12b is H.
  • G is CR 11a ; J is CR 11b ; L is CR 11c ; and K is N.
  • each of R 11a , R 11b , and R 11c is H.
  • each of R 12a , R 12b , and R 12c is H.
  • R 1a is H; W is C—H; Y, is C—H; Z is C—H; R 7 is H; R 8 is H; R 9 is H; R 10 is H; X is O, and q is 1.
  • R 2 is F.
  • R 3 is methoxy or ethoxy.
  • G is N; J is CR 11b ; L is CR 11c ; and K is CR 11d .
  • each of R 11b , R 11c , and R 11d is H.
  • each of R 12a , R 12b , and R 12c is H.
  • G is CR 11a ; J is N; L is CR 11c ; and K is CR 11d .
  • each of R 11a , R 11c , and R 11d is H.
  • each of R 12a , R 12b , and R 12c is H.
  • G is CR 11a ; J is CR 11b ; L is N; and K is CR 11d .
  • each of R 11a , R 11b , and R 11d is H.
  • each of R 12a , R 12b , and R 12c is H.
  • G is CR 11a ; J is CR 11b ; L is CR 11c ; K is CR 11d ; R 11a , R 11b , R 11c , and R 11d are H; R 1a is H; W is C—H; Z is C—H; R 2 is F; R 3 is methoxy; R 7 is H; R 8 is H; R 9 is H; R 10 is H; X is O; q is 1; and two of R 12a , R 12b , and R 12c are H and the other of R 12a , R 12b , and R 12c is F.
  • Y is N.
  • R 2 is selected from F, CF 3 , or (C 1 -C 6 )alkoxy. In some such embodiments, R 2 is selected from F, CF 3 , or (C 4 -C 6 )alkoxy. In some embodiments, R 2 is H or F. In other embodiments, R 2 is F. In still other embodiments, R 2 is H. In other embodiments, R 2 is propoxy, butoxy, or pentoxy. In some such embodiments, R 2 is butoxy.
  • A is selected from (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, —O—(C 1 -C 12 )alkyl, —O—(C 2 -C 12 )alkenyl, or —O—(C 1 -C 4 )alkyl-aryl.
  • R 2 is H or F
  • A is selected from a branched (C 4 -C 10 )alkyl group, a (C 4 -C 10 )alkenyl group, a bicyclic (C 7 -C 12 )alkyl group, an unsubstituted or a substituted (C 5 -C 7 )cycloalkyl group, or an unsubstituted or a substituted (C 5 -C 7 )cycloalkenyl group.
  • A is a an unsubstituted (C 5 -C 7 )cycloalkyl group, a (C 5 -C 7 )cycloalkyl group substituted with 1, 2, 3, or 4 methyl groups, an unsubstituted (C 5 -C 7 )cycloalkenyl group, or a (C 5 -C 7 )cycloalkenyl group substituted with 1, 2, 3, or 4 methyl groups.
  • R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopropylmethyl.
  • R 3 is methoxy.
  • A is selected from
  • A is selected from
  • R 3 is selected from —OH, —O(C 1 -C 2 )alkyl, or —S(C 1 -C 2 )alkyl. In some such embodiments, R 3 is selected from —O(C 1 -C 2 )alkyl or —S(C 1 -C 2 )alkyl. In some embodiments, R 3 is selected from —O-Me or —S-Me. In other such embodiments R 3 is —O-Et. In still other such embodiments, R 3 is selected from —O—(C 1 -C 2 )haloalkyl. Examples of some such groups include —OCF 3 and —OCH 2 CF 3 .
  • R 3 is selected from methoxy or ethoxy.
  • R 3 is a substituted (C 1 -C 2 )alkyl group such as a —CHF 2 or —CF 3 group.
  • R 3 is a (C 1 -C 3 )alkyl group that is substituted with a group such as —OH or with an oxo group. Examples of such groups include, but are not limited to, —C(CH 3 ) 2 OH and —C( ⁇ O)—CH 3 .
  • R 3 is selected from —F, —Cl, —OH, —OCH 3 , —SCH 3 , —OCH 2 CH 3 , —OCHF 2 , —OCF 3 , —OCH 2 CF 3 , —O-cyclopropyl, —CHF 2 , —CF 3 , —C( ⁇ O)—CH 3 , —CH(CH 3 ) 2 OH, or —CH 2 CH 3 .
  • R 3 is selected from —OCH 3 , —OCH 2 CH 3 , —OCHF 2 , —OCF 3 , —OCH 2 CF 3 , —O-cyclopropyl, —CHF 2 , or —CF 3 .
  • R 3 is selected from —F, —Cl, —OCHF 2 , —OCH 2 CF 3 , —OCF 3 , —O-cyclopropyl, —CF 3 , or —CHF 2 .
  • R 3 is selected from —OCHF 2 , —OCH 2 CF 3 , —OCF 3 , —O-cyclopropyl, —CF 3 , or —CHF 2 .
  • q is 1.
  • R 1a is H or methyl. In some such embodiments, R 1a is H.
  • R 1 and R 1a join together to form a ring having 3 to 7 ring members.
  • R 1 and R 1a join to form a cycloalkyl ring such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring.
  • the ring has 3 to 7 ring members and includes 1 heteroatom selected from O, S, or N.
  • W, Y, and Z are all C—H. In other embodiments W and Z are C—H and Y is N.
  • A is selected from (C 3 -C 10 )alkyl or (C 4 -C 10 )alkenyl. In some such embodiments, A is t-butyl. In other such embodiments, A is an unsubstituted or substituted cyclopentyl, cyclohexyl, or cycloheptyl group. In some such embodiments, A is an unsubstituted cyclopentyl, cyclohexyl, or cycloheptyl group.
  • A is a cyclopentyl, cyclohexyl, or cycloheptyl group optionally substituted with 1, 2, 3, or 4 (C 1 -C 4 )alkyl groups. In some such embodiments, A is a cyclopentyl, cyclohexyl, or cycloheptyl group substituted with a t-butyl group. In other such embodiments A is a cyclopentyl, cyclohexyl, or cycloheptyl group substituted with 1 or 2 methyl groups.
  • A is an unsubstituted or substituted cyclopentenyl, cyclohexenyl, or cycloheptenyl group. In some such embodiments, A is an unsubstituted cyclopentenyl, cyclohexenyl, or cycloheptenyl group. In some such embodiments, A is a cyclopentenyl, cyclohexenyl, or cycloheptenyl group optionally substituted with 1, 2, 3, or 4 (C 1 -C 4 )alkyl groups.
  • A is a cyclopentenyl, cyclohexenyl, or cycloheptenyl group substituted with a t-butyl group. In other such embodiments A is a cyclopentenyl, cyclohexenyl, or cycloheptenyl group substituted with 1 or 2 methyl groups.
  • A is selected from
  • A is selected from any one or more of
  • A is a group of formula A′.
  • R 4 , R 5 , and R 6 are independently selected from H, F, (C 1 -C 4 )alkyl, and two of R 4 , R 5 , and R 6 are other than H; or two or three of R 4 , R 5 , and R 6 join together to form an optionally substituted saturated or partially unsaturated 3-8 membered monocyclic or bicyclic ring.
  • R 4 , R 5 , and R 6 are independently selected from H and (C 1 -C 4 )alkyl groups and at least two of R 4 , R 5 , and R 6 are (C 1 -C 4 )alkyl groups.
  • all three of R 4 , R 5 , and R 6 are independently selected from (C 1 -C 4 )alkyl groups. In some such embodiments, two of R 4 , R 5 , and R 6 are methyl groups. In some such embodiments, each of R 4 , R 5 , and R 6 is a methyl group.
  • R 4 , R 5 , and R 6 are independently selected from H, (C 1 -C 4 )alkyl groups, or a substituted (C 1 -C 4 )alkyl group selected from (C 1 -C 4 )haloalkyl groups, (C 1 -C 4 )perhaloalkyl groups, or (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl groups.
  • at least one of R 4 , R 5 , and R 6 is a CF 3 group.
  • at least one of R 4 , R 5 , and R 6 is a methoxymethyl group.
  • A is a group of formula A′ where the wavy line indicates the point of attachment and R 4 , R 5 , and R 6 are independently selected from H, F, OH, —O—(C 1 -C 3 )alkyl, (C 1 -C 6 )alkyl and (C 2 -C 6 )alkenyl, and two of R 4 , R 5 , and R 6 are other than H; or two or three of R 4 , R 5 , and R 6 join together to form an optionally substituted saturated or partially unsaturated 3-8 membered monocyclic or bicyclic ring.
  • R 4 , R 5 , and R 6 are independently selected from H, OH, OMe, OEt, (C 1 -C 6 )alkyl, and (C 2 -C 6 )alkenyl groups and at least two of R 4 , R 5 , and R 6 are (C 1 -C 4 )alkyl groups. In some such embodiments, all three of R 4 , R 5 , and R 6 are independently selected from (C 1 -C 4 )alkyl groups. In some such embodiments, two of R 4 , R 5 , and R 6 are methyl groups. In some such embodiments, each of R 4 , R 5 , and R 6 is a methyl group.
  • R 4 , R 5 , and R 6 are independently selected from H, (C 1 -C 4 )alkyl groups, or a substituted (C 1 -C 4 )alkyl group selected from (C 1 -C 4 )haloalkyl groups, (C 1 -C 4 )perhaloalkyl groups, or (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl groups.
  • at least one of R 4 , R 5 , and R 6 is a CF 3 group.
  • at least one of R 4 , R 5 , and R 6 is a methoxymethyl group.
  • At least one of R 4 , R 5 , and R 6 is selected from OH, methoxy, or is ethoxy. In some such embodiments one of R 4 , R 5 , and R 6 is a methoxy. In other such embodiments one of R 4 , R 5 , and R 6 is OH. In other such embodiments one of R 4 , R 5 , and R 6 is ethoxy.
  • R 4 , R 5 , and R 6 together with the C atom to which they are attached, join to form a 3-8 or 3-7 membered ring, and the other of R 4 , R 5 , and R 6 is selected from H, an unsubstituted (C 1 -C 4 )alkyl, or a substituted (C 1 -C 4 )alkyl.
  • the ring is a carbocyclic ring which may be a fully saturated cycloalkyl ring.
  • the 3-8 membered ring is a 5-7 membered ring, a 3-6 membered ring, or a 3-5 membered ring.
  • examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl rings.
  • two of R 4 , R 5 , and R 6 join to form a cyclopropyl ring.
  • the other of R 4 , R 5 , and R 6 is H.
  • R 4 , R 5 , and R 6 together with the C atom to which they are attached, join to form an optionally substituted saturated or partially unsaturated 3-8 or 3-7 membered ring which may be monocyclic or bicyclic, and the other of R 4 , R 5 , and R 6 is selected from H, an unsubstituted (C 1 -C 4 )alkyl, or a substituted (C 1 -C 4 )alkyl.
  • the ring only includes carbon ring members.
  • the ring includes 0 or 1 double bonds between ring members.
  • the 3-7 membered ring is a 3-6, or a 3-5 membered ring.
  • Such rings include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl rings.
  • two of R 4 , R 5 , and R 6 join to form an optionally substituted cyclopropyl ring.
  • the other of R 4 , R 5 , and R 6 is H.
  • two of R 4 , R 5 , and R 6 join to form an optionally substituted cyclopentenyl, cyclohexenyl, or cycloheptenyl ring.
  • R 4 , R 5 , and R 6 are H. In some embodiments all three of R 4 , R 5 , and R 6 , together with the C atom to which they are attached, join to form an optionally substituted saturated or partially unsaturated 3-8 membered ring bicyclic ring system.
  • A may comprise an adamantyl or another bicyclic ring system such as, but not limited to bicyclo[3.2.1]octane, bicyclo[2.2.1]heptane, and the like.
  • the ring only includes carbon ring members. In some such embodiments, the ring includes 0 or 1 double bonds between ring members.
  • A is a branched chain (C 4 -C 8 )alkyl group such as a t-butyl group.
  • A is an optionally substituted (C 5 -C 7 )cycloalkyl group or an optionally substituted (C 5 -C 7 )cycloalkenyl group.
  • the (C 5 -C 7 )cycloalkyl group or the (C 5 -C 7 )cycloalkenyl group are substituted with 1, 2, 3, or 4 methyl groups.
  • A has the formula
  • A has the formula
  • A has the formula
  • A has the formula
  • A is an —OR 4a group.
  • R 4a is selected from a methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, t-butyl, or an isomer thereof.
  • R 4a is selected from such an alkyl group that is substituted.
  • R 4a may a trihaloalkyl group such as a CF 3 group or another perhaloalkyl group.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is selected from
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is a (C 1 -C 12 )alkyl or is a (C 2 -C 12 )alkenyl group and the (C 1 -C 12 )alkyl or the (C 2 -C 12 )alkenyl group is substituted with at least one A′′ group where A′′ is selected from —F, —OH, —O—(C 1 -C 4 )alkyl, —O(C 1 -C 4 )alkyl-aryl, —O(C 2 -C 8 )alkenyl, or —O—(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl. Therefore, in some embodiments A is selected from any one or all of:
  • A is selected from
  • A is selected from
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is selected from
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 2 is F or butoxy. In some such embodiments, R 2 is F whereas in other such embodiments, R 2 is butoxy. In still other embodiments, R 2 is propoxy, pentoxy, or hexoxy. In still further embodiments, R 2 is selected from F or (C 3 -C 4 )alkoxy. In some embodiments, R 2 is a —CF 3 group.
  • R 3 is methoxy or ethoxy. In some such embodiments, R 3 is methoxy.
  • R 3 is a substituted or unsubstituted —O(C 1 -C 2 )alkyl group. In some such embodiments, R 3 is a —OCHF 2 group.
  • X is O. In other embodiments, X is S.
  • R 7 and R 8 are both H. In some embodiments one of R 7 and R 8 is H and the other of R 7 and R 8 is methyl. Therefore, in some embodiments R 7 and R 8 are independently selected from H and methyl.
  • R 9 and R 10 are both H. In other embodiments, R 9 and R 10 are selected from H and methyl. In some such embodiments, one of R 9 and R 10 is H and the other of R 9 and R 10 is methyl.
  • R 1 is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heterocyclyl, or heteroaryl. In some such embodiments, R 1 is a (C 1 -C 4 )alkyl. In some such embodiments, R 1 is a methyl, ethyl, propyl, or butyl group. In some such embodiments, R 1 is a methyl, ethyl, or propyl. In some such embodiments, R 1 is a propyl group.
  • R 1 is a (C 3 -C 6 )alkyl group that is a cycloalkyl group such as cyclopropyl, cyclobutyl, or cyclopentyl group.
  • R 1 is a CF 3 group.
  • R 1 is a —CH 2 CF 3 group.
  • R 1 is a —CH 2 CH 2 CF 3 group.
  • R 1 is a cyclopropyl group or a cyclobutyl group that is optionally substituted.
  • R 1 is selected from a cyclopropyl group that is optionally substituted with one or two methyl groups.
  • R 1 is a cyclobutyl group that is optionally substituted with one or two methyl groups.
  • R 1 is a cyclopropylmethyl (—CH 2 (cyclopropyl)) group.
  • R 1 is a cyclobutylmethyl (—CH 2 (cyclobutyl)) group.
  • R 1 is a —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —C(H)(CH 3 ) 2 , —CH ⁇ CH 2 , —C(CH 3 ) ⁇ CH 2 , —CH 2 C(H) ⁇ CH 2 , —CF 3 , —CH 2 CH 2 CF 3 , -cyclopropyl, -cyclobutyl, —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 —O—CH 3 , —CH ⁇ CHCH 2 CH 3 , or —CH 2 CH(CH 3 ) 2 .
  • R 1a is —H whereas in other such embodiments, R 1a is —CH 3 .
  • R 1 is a cis(C 2 -C 6 )alkenyl group whereas in other embodiments R 1 is a trans(C 2 -C 6 )alkenyl group. In some embodiments, R 1 is a mixture of cis and trans(C 2 -C 6 )alkenyl groups. In other embodiments, R 1 is a (C 2 -C 4 )alkenyl group. In some embodiments R 1 is a cis(C 2 -C 4 ) alkenyl group whereas in other embodiments R 1 is a trans(C 2 -C 4 )alkenyl group.
  • R 1 is a mixture of cis and trans(C 2 -C 4 )alkenyl groups. In some embodiments, R 1 is selected from —CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —CH ⁇ CH—CH 2 —CH 3 , or —CH 2 —CH ⁇ CH 2 . In some such embodiments, R 1 is —CH 2 —CH ⁇ CH 2 . In some such embodiments, R 1 is —CH ⁇ CH—CH 3 . In some such embodiments, R 1 has the formula
  • R 1 has the formula
  • R 1 is a (C 2 -C 4 ) alkynyl.
  • R 1 is —C ⁇ C—CH 3 .
  • G is CR 11a ; J is CR 11b ; L is CR 11c ; K is CR 11d ; R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , and R 12c are all H; R 1a is H; W is C—H; Y, is C—H; Z is C—H; R 2 is F; R 3 is methoxy; R 7 is H; R 8 is H; R 9 is H; R 10 is H; X is O, and q is 1.
  • A is a branched chain (C 4 -C 8 )alkyl group such as a t-butyl, —CH 2 CH 2 C(CH 3 ) 3 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(cyclopropyl), or —C(CH 3 ) 2 CH 2 CH 2 CH 3 group.
  • A is a t-butyl group.
  • A is an optionally substituted (C 5 -C 7 )cycloalkyl group or an optionally substituted (C 5 -C 7 )cycloalkenyl group.
  • the (C 5 -C 7 )cycloalkyl group or the (C 5 -C 7 )cycloalkenyl group are substituted with 1, 2, 3, or 4 methyl groups.
  • A has the formula
  • A has the formula
  • A is a (C 4 -C 10 )alkenyl group. In some such embodiments, A is selected from —CH ⁇ CH—C(CH 3 ) 3 , —CH ⁇ CH—CH 2 CH 2 CH 3 , —CH ⁇ CH-cyclopropyl, or —CH ⁇ CH-cyclohexyl groups.
  • G is CR 11a ; J is CR 11b ; L is CR 11c ; K is CR 11d ; R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , and R 12c are all H; R 1a is H; W is C—H; Y, is C—H; Z is C—H; R 2 is F; R 3 is methoxy; R 7 is H; R 8 is H; R 9 is H; R 10 is H; X is O, q is 1, and A is —O—(C 1 -C 12 )alkyl, —O—(C 2 -C 12 )alkenyl, or —O—(C 1 -C 4 )alkyl-aryl.
  • A is a —OCH 2 -phenyl. In other embodiments, A is a —O—CF 3 . In other such embodiments, A is a —O—(C 3 -C 10 )alkyl or —O—(C 3 -C 10 )alkenyl group. In other such embodiments, A is —O—(C 3 -C 8 )cycloalkyl optionally substituted with 1 or 2 methyl groups. In some such embodiments, A is an unsubstituted —O—(C 3 -C 8 )cycloalkyl group.
  • A is a cyclopropyloxy, a cyclobutyloxy, a cyclopentyloxy, a cyclohexyloxy, or a cycloheptyloxy group.
  • A is a —O—CH 2 CH 2 CH 3 , —O—CH 2 CH 2 CH 2 CH 3 , —O—CH 2 CH 2 CH 2 CH 2 CH 3 , —O—CH(CH 3 ) 2 , or —O—CH 2 CH(CH 3 ) 2 .
  • R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , and R 12c are all H; R 1a is H; W is C—H; Y, is C—H; Z is C—H; R 7 is H; R 8 is H; R 9 is H; R 10 is H; X is O; and A is —OR 4a .
  • q is 1.
  • G is CR 11a ; J is CR 11b ; L is CR 11c ; K is CR 11d ; R 11a is H or F; R 11b , R 11c , and R 11d are H; R 1a is H; W is C—H; Z is C—H; R 2 is F; R 3 is methoxy; R 7 is H; R 8 is H; R 9 is H; R 10 is H; X is O; q is 1; and two of R 12a , R 12b , and R 12c are H and the other of R 12a , R 12b , and R 12c is F.
  • R 11a is H whereas in other such embodiments, R 11a is F.
  • the compound of formula I or I′ is a compound of formula II or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula II has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • the compound of formula II is a compound of formula II′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula II′ has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • the compound of formula II is a compound of formula II′′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula II′ has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • W and Z are CH and Y is N such that the compound of formula I has the formula III or is a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula III has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • the compound of formula III is a compound of formula III′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or mixture thereof.
  • the compound of formula III′ has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • the compound of formula III is a compound of formula III′′ or a pharmaceutically acceptable salt, stereoisomer, C 1 -C 6 alkyl ester, or a mixture thereof.
  • the compound of formula III′′ has the following structure where each of the variables has any of the values of any of the embodiments described herein:
  • R 11a is selected from H or F.
  • R 11a is H whereas in other such embodiments R 11a is F.
  • R 11b , R 11c , and R 11d are each H.
  • R 11a is F
  • R 11b is H
  • R 11c is H
  • R 11d is H whereas in other embodiments R 11a is H
  • R 11b is H
  • R 11c is H
  • R 11d is H.
  • R 2 is F.
  • R 3 is methoxy (—OCH 3 ).
  • one of R 12a , R 12b , and R 12c is F and the other two of R 12a , R 12b , and R 12c are H.
  • R 12c is F
  • R 12a is H
  • R 12b is H
  • each of R 12a , R 12b , and R 12c is H.
  • X is selected from O or S. Therefore, in some embodiments, X is O whereas in other embodiments, X is S.
  • the compound of formula I is selected from a group that includes each, all, or any one of the compounds in any of the tables or is a pharmaceutically acceptable salt, or C 1 -C 6 alkyl ester thereof.
  • the compound exists as a single enantiomer whereas in other embodiments, the compound is a mixture of enantiomers of the compounds shown above.
  • the compound of formula I is one of the compounds in any of the tables or is a pharmaceutically acceptable salt, or C 1 -C 6 alkyl ester thereof.
  • the compound is an enantiomer or diastereomer of one of the compounds in any of the tables or is a pharmaceutically acceptable salt, or C 1 -C 6 alkyl ester thereof.
  • the compound of formula I is a C 1 -C 6 alkyl ester.
  • esters typically have the formula IE where each of the variables has any of the values set forth herein with respect to any of the embodiments, and Alk is a C 1 -C 6 alkyl group.
  • Alk is a methyl or ethyl group such that the compound is a methyl or ethyl ester.
  • the compound is selected from any of those in any of the tables.
  • the compound of formula I has a variable corresponding to any of the groups in the compounds of any of the tables. For example, if a compound in any of the tables has a group corresponding to the A group, then in some embodiments of the compound of formula I, the A group will correspond to that set forth in the compound(s) in any of the tables.
  • the compound of any of the embodiments described herein does not displace a compound of the following formula that is bound to the GPR40 receptor
  • the compound of any one of the embodiments described herein binds to a different site on the GPR40 receptor than does a compound of formula
  • the invention provides a compound that binds to a different site on the GPR40 receptor than does the following compound
  • the compound is a synthetic compound that does not occur naturally in the body of an animal.
  • the compound comprises a biphenyl group.
  • the compound comprises a biphenyl group and a phenyl group that is not part of the biphenyl group.
  • the compound further comprises a carboxylic acid group or a salt of such a group.
  • the phenyl group that is not part of the biphenyl group is meta substituted.
  • the compound of any of the embodiments is a salt. In other embodiments, the compound of any of the embodiments is a C 1 -C 6 alkyl ester. In some such embodiments, the C 1 -C 6 alkyl ester is a C 1 -C 6 alkyl ester such as a methyl, ethyl, propyl, butyl, isopropyl, pentyl, or hexyl ester. In other embodiments, the C 1 -C 6 alkyl ester is a methyl, ethyl, propyl, or butyl ester. In some such embodiments, the ester is a methyl or ethyl ester.
  • the compound comprises a stereomerically pure S-enantiomer. In other embodiments, the compound comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound comprises a mixture of S- and R-enantiomers.
  • the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent, or excipient, and a compound of any of the embodiments of the invention.
  • a compound of any of the embodiments described herein is used to prepare a medicament.
  • the invention provides a therapeutic composition that includes a compound of any of the embodiments and a second therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in the treatment of a disease or condition mediated by GPR40.
  • the disease or condition is type II diabetes.
  • the second therapeutic agent is selected from metformin, a thiazolidinedione, or a DPP-IV inhibitor.
  • the compound of any of the embodiments described herein and the second therapeutic agent are provided as single composition.
  • the compound of any of the embodiments described herein and the second therapeutic agent are provided separately as parts of a kit.
  • the invention provides a compound of any of the embodiments described herein for use as a medicament.
  • the invention provides a compound of any of the embodiments described herein for use in modulating GPR40.
  • the invention provides a compound of any of the embodiments described herein for use in treating a disease or condition selected from type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, or edema.
  • the compound is used for treating type II diabetes.
  • the compounds of the invention have been found to stimulate GLP-secretion.
  • Cells contacted with compounds of the invention have been found to increase GLP-1 secretion. Therefore, in some embodiments, the invention provides a method of stimulating GLP-1 secretion by cells. Such methods typically include contacting a cell capable of producing GLP-1 with a compound of any of the embodiments set forth herein.
  • Administration of the compounds of the invention to subjects has also been found to provide increased levels of GLP-1 in the blood plasma of such subjects. Therefore, in some embodiments, a compound of any of the embodiments described herein may be used to stimulate GLP-1 secretion and increase the blood plasma level of GLP-1 in a subject.
  • the compounds of the invention both stimulate GLP-1 secretion and activate GPR40. Therefore, in some embodiments, the compounds of the invention both stimulate GLP-1 secretion and display incretin effect by activating GPR40.
  • the invention further provides a method for increasing GLP-1 levels in the blood plasma of a subject.
  • Such methods typically include administering a compound of any of the embodiments to a subject.
  • the subject is a diabetic patient.
  • the subject is an obese patient.
  • the compounds of the invention may be administered in the fasted or non-fasted state. Therefore, in some embodiments, a compound of any of the embodiments is administered to a subject prior to a meal. In some such embodiments, the compound is administered 2 hours, 1, hour, 30 minutes, or 15 minutes before a meal. In other embodiments, a compound of any embodiments set forth herein is administered to a subject during a meal. In other embodiments, a compound of any of the embodiments described herein is administered to a subject within 2 hours, within 1 hour, within 30 minutes, or within 15 minutes of a meal.
  • the invention provide a process for hydrogenating a compound of formula V, the method comprising: (a) reacting a compound of formula V with H 2 in the presence of a transition metal or a transition metal complex to form a compound of formula VIA, a compound of formula VIB or mixture of the compound of formula VIA and the compound of formula VIB.
  • the compounds of formula V, VIA, and VIB have the following structures:
  • the invention provides a compound of formula V, VIA, and/or VIB.
  • the variables have the definitions provided herein with respect to the process for hydrogenating a compound of formula V.
  • the variables have any of the definitions provided with respect to any of the embodiments of the process for hydrogenating a compound of formula V.
  • R 14 is OH.
  • R 15 and R 16 are both methyl groups.
  • the transition metal or transition metal complex comprises palladium, platinum, nickel, or rhodium.
  • the reduction may be accomplished using palladium on carbon, Raney nickel, PtO 2 or various rhodium compounds.
  • the transition metal or transition metal complex is palladium, and in some such embodiments is palladium on carbon.
  • Various supported catalysts known to those skilled in the art may be used in conjunction with this process.
  • the process is an enantioselective process.
  • the method includes reacting a compound of formula V with H 2 in the presence of a transition metal or a transition metal complex and a phosphine ligand to form a compound of formula VIA, a compound of formula VIB, or a mixture of the compound of formula VIA and the compound of formula VIB.
  • the phosphine ligand comprises at least one chiral center.
  • R 14 is —OH.
  • R 15 and R 16 are both —CH 3 .
  • n 1
  • R 12b and R 12c are both —H.
  • R 12a is H or halo.
  • R 12a is H whereas in other embodiments, R 12a is F.
  • the transition metal or the transition metal complex comprises rhodium.
  • the transition metal complex is generated from Rh(COD) 2 BF 4 , Rh(COD) 2 SbF 6 , or Rh(NBD) 2 BF 4 where COD represents the 1,5-cyclooctadiene ligand and NBD represents the norbornadiene ligand.
  • the phosphine is a diphosphine.
  • the diphosphine comprises a ferrocene group.
  • the diphosphine is selected from
  • the diphosphine is an enantiomer of one of the compounds shown above.
  • the compound of formula V is reacted with H 2 at a pressure of from 15 to 1400 psi. In some such embodiments, the pressure ranges from 50 to 400 psi.
  • the compound of formula V is reacted with H 2 in a mixture comprising at least one solvent selected from an ethereal solvent, an ester solvent, an aromatic solvent, a halogenated hydrocarbon solvent, a ketone solvent, or a C 1 -C 4 alcohol solvent.
  • the at least one solvent comprises an ethereal solvent selected from tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydropyran, diethylether, dipropylether, or dibutylether.
  • the at least one solvent comprises tetrahydrofuran. In other such embodiments, the at least one solvent comprises at least one of tetrahydrofuran, toluene, acetone, methyl ethyl ketone, ethanol, or methanol.
  • the transition metal complex is mixed with the phosphine in a solvent prior to adding the compounds of formula V.
  • the solvent is an ethereal solvent such as tetrahydrofuran
  • the transition metal complex is selected from Rh(COD) 2 BF 4 , Rh(COD) 2 SbF 6 , or Rh(NBD) 2 BF 4 .
  • the phosphine is a diphosphine comprising a ferrocenyl group such as one of those described herein.
  • the compound of formula I is reacted with H 2 at a temperature ranging from 15° C. to 60° C. In some such embodiments, the temperature ranges from 20° C. to 45° C.
  • the enantiomeric excess of one of the products is greater than 50%, greater than 60%, greater than 75%, greater than 85%, greater than 90%, greater than 95%, or greater than 98%.
  • the conversion of the compound of formula V to the compound of formula VIA, the compound of formula VIB, or the mixture of the compound of formula VIA and the compound of formula VIB is greater than 50%, greater than 70%, greater than 80%, or greater than 95%.
  • Scheme 1 provides a general synthetic scheme for exemplary compounds of the invention utilizing ester A where the variables in Scheme 1 have any of the values described above with respect to any of the embodiments, V is a OH or a halogen such as, but not limited to a Cl, Br, or I, or sulfonate ester such as, but not limited to OTs (tosylate) or OTf (triflate); and Alk is a straight or branched chain alkyl group having from 1-8 carbon atoms.
  • protecting groups may be necessary for the preparation of certain compounds and will be aware of those conditions compatible with a selected protecting group.
  • protecting groups include, for example, those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999). Accordingly, the exemplary methods and the examples described herein are illustrative of the present invention and are not to be construed as limiting the scope thereof.
  • Certain compounds of the invention that include a compound with an A group that is a cycloalkyl ring possessing a chiral center can be produced using a hydrogenation process that has been discovered.
  • a cycloalkenyl aryl compound such as a compound of formula V can be hydrogenated to provide the two cycloalkyl enantiomers VIA and VIB.
  • the process includes: (a) reacting a compound of formula V with H 2 in the presence of a transition metal or a transition metal complex to form a mixture of a compound of formula VIA and a compound of formula VIB.
  • the compounds of formula V, VIA, and VIB have the structures shown below with respect to the enantioselective hydrogenation process.
  • the transition metal or transition metal complex comprises palladium, platinum, nickel, or rhodium.
  • the reduction may be accomplished using palladium on carbon, Raney nickel, PtO 2 or various rhodium compounds.
  • Various supported catalysts known to those skilled in the art may be used in conjunction with this process.
  • Certain compounds of the invention that include a compound with an A group that is a cycloalkyl ring possessing a chiral center can also be produced using an enantioselective hydrogenation process that has been discovered.
  • a cycloalkenyl aryl compound such as a compound of formula V can be hydrogenated to provide the two cycloalkyl enantiomers VIA and VIB.
  • the method includes reacting a compound of formula V with H 2 in the presence of a transition metal or a transition metal complex and a phosphine ligand to form a compound of formula VIA, a compound of formula VIB, or a mixture of a compound of formula VIA and a compound of formula VIB.
  • R 12a is selected from —H, halo, a —(C 1 -C 6 )alkyl group, or a —O—(C 1 -C 6 )alkyl group
  • R 12b is selected from —H, halo, a —(C 1 -C 6 )alkyl group, or a —O—(C 1 -C 6 )alkyl group
  • R 12c is selected from —H, halo, a —(C 1 -C 6 )alkyl group, or a —O—(C 1 -C 6 )alkyl group
  • R 14 is —H or —OH
  • R 15 is selected from —H, or a —(C 1 -C 6 )alkyl group
  • R 16 is selected from —H, or a —(C 1 -C 6 )alkyl group
  • R 17a is a —(C 1 -C 6
  • R 15 or R 16 is a —(C 1 -C 6 )alkyl group.
  • R 15 and R 16 are both —CH 3 .
  • the subscript n is 1.
  • R 12b and R 12c are both —H.
  • R 12a is H or halo.
  • R 12a is H whereas in other embodiments, R 12a is F.
  • Typical solvents for the reaction include ethereal solvents, ester solvents, aromatic solvents, halogenated hydrocarbon solvents, ketone solvents, and C 1 -C 4 alcohol solvents.
  • ethereal solvents include, but are not limited to cyclic and non-cyclic ethers including, but not limited to, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, tetrahydropyran, diethylether, dipropylether, and dibutylether.
  • Tetrahydrofuran is an example of one solvent that has been found to function particularly well, but other solvents such as toluene, acetone, methyl ethyl ketone, dichloromethane, ethanol, and methanol may be employed in the reduction.
  • the enantioselective hydrogenation process may be conducted at various temperatures.
  • the compound of formula V is reacted with H 2 at a temperature ranging from 15° C. to 60° C. In some such embodiments, the temperature ranges from 20° C. to 45° C.
  • the enantioselective hydrogenation process may also be conducted at various pressures of H 2 .
  • the compound of formula V is reacted with H 2 at a pressure of from 15 to 1400 psi.
  • the pressure is from 50 to 400 psi whereas in other embodiments, the pressure ranges from 80 to 400 psi, from 100 to 400 psi, or from 100 to 200 psi.
  • the phosphine is a diphosphine.
  • the diphosphine comprises a ferrocene group. Examples of diphosphines comprising a ferrocene group include, but are not limited to,
  • diphosphine has been fount to be particularly effective. Therefore, in some embodiments, the diphosphine is
  • the diphosphine is an enantiomer of one of those shown above.
  • transition metals and transition metal complexes may be used to hydrogenate compounds of formula V.
  • rhodium has been found to produce particularly good results. Therefore in some embodiments for hydrogenating a compound of formula V, the transition metal or the transition metal complex comprises rhodium.
  • the transition metal or transition metal complex is generated from Rh(COD) 2 BF 4 , Rh(COD) 2 SbF 6 , or Rh(NBD) 2 BF 4 .
  • the transition metal complex is mixed with the phosphine in a solvent prior to adding the compounds of formula V.
  • the solvent is an ethereal solvent such as tetrahydrofuran
  • the transition metal complex is selected from Rh(COD) 2 BF 4 , Rh(COD) 2 SbF 6 , or Rh(NBD) 2 BF 4 .
  • the phosphine is a diphosphine comprising a ferrocenyl group such as one of those described herein.
  • R 12a is F.
  • a yield of 83% and a 99.3% enantiomeric excess was achieved after 2 hours at room temperature under 200 psi H 2 when the compound shown in Scheme 3 (R 12a ⁇ F) and triethylamine were added to the mixture prepared by mixing Rh(COD) 2 BF 4 and (R)-1-[(S)-2-(R)-(ditertbutylphosphino)ferrocenyl]ethyl-bis-(3,5-bistrifluoromethylphenyl)phosphine in tetrahydrofuran.
  • trialkyl amine base such as triethylamine was found to slightly improve the enantiomeric excess in these reactions. While the trialkylamine was not required for the reaction to proceed with good enantioselectivity, it was found to improve the ee in cases where the starting material may have contained small amounts of impurities.
  • the enantiomeric excess of one of the products is greater than 50%, greater than 60%, greater than 75%, greater than 85%, greater than 90%, greater than 95%, or greater than 98%.
  • the conversion of the compound of formula V to the compound of formula VIA, the compound of formula VIB, or the mixture of the compound of formula VIA and the compound of formula VIB is greater than 50%, greater than 70%, greater than 80%, or greater than 95%.
  • Compounds of formula VIA and VIB may be used to synthesize the biphenyl tail groups used to prepare the example compounds of the present invention. Therefore, in some embodiments, where R 14 is —OH (compounds of formula VIA′ and VIB′) compounds of formula VIA′ and/or VIB′ are converted to compounds of VIIA and/or VIIB as shown in Scheme 4 by reacting them with N-phenyl-bis(trifluoromethanesulfonimide) or with trifluoromethanesulfonic anhydride. Typically, this reaction is accomplished in a suitable solvent such as dichloromethane with triethylamine and dimethylaminopyridine.
  • a suitable solvent such as dichloromethane with triethylamine and dimethylaminopyridine.
  • the process further includes reacting a compound of formula VIA′ and/or VIB′ with N-phenyl-bis(trifluoromethanesulfonimide) or with trifluoromethanesulfonic an hydride to form a compound of formula VIIA or VIIB where the variables have any of the values set forth herein.
  • Compounds of formula VIIA and VIIB are very useful intermediates and can be used to synthesize numerous biphenyl or phenylpyridyl compounds that may be used to construct the compounds of the invention.
  • compounds VIIA and VIIB can be reacted with boronic acids or boronates (VIIIA or VIIIB) to provide biphenyl compounds IXA or IXB using the conditions set forth herein. Therefore, in some embodiments, the process further includes reacting a compound of formula VIIA and/or VIIB with a compound of formula VIIIA or VIIIB to form a compound of formula IXA or IXB where the variables have any of the values set forth herein.
  • compounds IXA and IXB can be reduced with reducing agents such as lithium aluminum hydride using the conditions set forth herein to provide hydroxymethyl compounds XA or XB which may then be converted to halomethyl compounds with reagents such as thionyl chloride to provide compounds such as XIA or XIB where the variables have any of the values set forth herein.
  • the method further comprising reducing a compound of formula IXA or IXB with a reducing agent such as LAH to form a compound of formula XA or XB.
  • the method further comprises converting the hydroxyl functional group of a compound of formula XA or XB to a chloride or a bromide to form a compound of formula XIA or XIB.
  • the method further includes reacting a compound of formula XA or XB or a compound of formula XIA or XIB with a compound of formula XII to form a compound of formula XIIIA or XIIIB.
  • Esters XIIIA and XIIIB which are compounds of formula I, can then be saponified using the conditions described herein to form compounds of formula XIVA and XIVB where the variables have any of the values set forth herein. Therefore, some embodiments include saponifying a compound of formula XIIIA or XIIIB to form a compound of formula XIVA or XIVB where R 18 is a (C 1 -C 6 )alkyl group and the other variables have any of the values set forth herein.
  • the invention provides pharmaceutical compositions suitable for pharmaceutical use comprising one or more compounds of the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant that the carrier, excipient, or diluent is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof.
  • Composition formulation may improve one or more pharmacokinetic properties (e.g., oral bioavailability, membrane permeability) of a compound of the invention (herein referred to as the active ingredient).
  • pharmacokinetic properties e.g., oral bioavailability, membrane permeability
  • compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. Nos. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • topical application For topical use, creams, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the invention are employed. As used herein, topical application is also meant to include the use of mouthwashes and gargles.
  • compositions and methods of the invention may further comprise other therapeutically active compounds, as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
  • other therapeutically active compounds as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidos
  • the invention provides methods of treating a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
  • the methods comprise administering to a subject in need thereof, a therapeutically effective amount of a compound or composition of any of the embodiments of the invention.
  • the disease or condition is type II diabetes.
  • the present invention provides a method for treating a disease or condition responsive to the modulation of GPR40.
  • Such methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
  • the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
  • the disease or condition is type II diabetes.
  • the disease or condition is obesity.
  • the disease or condition is hypertension.
  • the compound or composition is administered orally, parenterally, or topically. In some embodiments, the compound or composition is administered orally. In other embodiments, the compound or composition is administered parenterally. In other embodiments, the compound or composition is administered topically.
  • the compounds of the invention may be administered alone or in combination with one or more other therapeutic agents. Therefore, in some embodiments, the compound or composition of any of the embodiments is administered in combination with a second therapeutic agent.
  • the second therapeutic agent is an insulin sensitizing agent, such as metformin or a thiazolidinedione, for example.
  • the second therapeutic agent is a GLP-1 analog.
  • the second therapeutic agent is an inhibitor of DPP-IV such as, but not limited to, sitagliptin.
  • the invention provides methods of treating a disease or disorder responsive to modulation of GPR40 comprising administering to a subject having such a disease or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
  • the invention provides methods of treating a GPR40-mediated condition, disease or disorder comprising administering to a subject having such a condition, disease or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
  • the invention provides methods of modulating GPR40 comprising contacting a cell with one or more of the subject compounds or compositions.
  • a cell that constitutively expresses GPR40 is contacted with one or more of the subject compounds or compositions.
  • a cell to be contacted can be made to express or overexpress GPR40, for example, by expressing GPR40 from heterologous nucleic acid introduced into the cell or, as another example, by upregulating the expression of GPR40 from nucleic acid endogenous to the cell.
  • the compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal, local) routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the invention also contemplates administration of the compounds of the invention in a depot formulation, in which the active ingredient is released over a defined time period.
  • an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range, the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
  • the compositions are preferably provided in the form of tablets containing from 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 3.0, 5.0, 10.0, 15.0.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compounds of the invention can be combined or used in combination with other agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds of the invention are useful, including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
  • agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds of the invention are useful including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,
  • Such other agents, or drugs may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with a compound of the invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred.
  • the pharmaceutical compositions of the invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound of the invention.
  • therapeutic compositions that include a compound of the invention and a second therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of a subject with a disease or condition mediated by GPR40.
  • therapeutic compositions are provided that include a compound of the invention and a second therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the prophylactic treatment of a subject at risk for a disease or condition mediated by GPR40.
  • the components are provided as a single composition.
  • the compound and the second therapeutic agent are provided separately as parts of a kit.
  • Examples of other therapeutic agents that may be combined with a compound of the invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) cholesterol lowering agents such as HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (e.g., cholestyramine and colestipol), vitamin B 3 (also known as nicotinic acid, or niacin), vitamin B 6 (pyridoxine), vitamin B 12 (cyanocobalamin), fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate and benzafibrate), probucol, nitroglycerin, and inhibitors of cholesterol absorption (e.g., beta-sitosterol and acylCoA-cholesterol acyltransferase (ACAT
  • a compound of the invention may be administered along with a DPP-IV inhibitor or a GLP-I analog.
  • a compound of the invention is administered with any of the DPP-IV inhibitors set forth in U.S. Patent Publication No. 2006/0270701 which is hereby incorporated by reference in its entirety and for all purposes as if specifically set forth herein.
  • the weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Combinations of a compound of the invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the present invention provides a method for modulating circulating insulin concentration in a subject, comprising administering a compound or composition of the invention.
  • the insulin concentration is increased after the compound is administered to the subject.
  • the insulin concentration is decreased after the compound is administered to the subject.
  • a compound of composition of any of the described embodiments is used for treating a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.
  • the disease or condition is type II diabetes.
  • the compounds of the invention may also be used to modulate GPR 40. Therefore, in some embodiments, a compound or composition of any of the embodiments is used for modulating GPR40.
  • the compounds of any of the embodiments described herein may be used to prepare medicaments for treating the diseases or conditions described herein such as type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and/or edema.
  • the disease or condition is type II diabetes.
  • the compounds of any of the embodiments may also be used to prepare medicaments for modulating GPR40 in a subject such as in a mammalian subject with type II diabetes.
  • 2-Butoxy-5-methoxyphenylboronic acid (4.2). To a ⁇ 78° C. solution of 2-bromo-1-butoxy-4-methoxybenzene 4.1 (250 mg, 965 ⁇ mol) in THF (8.0 mL) was added tert-butyllithium, 1.7 M solution in pentane (1248 ⁇ L, 2122 ⁇ mol) dropwise under a blanket of nitrogen. The pale yellow solution was stirred for 0.5 h at ⁇ 78° C. before dropwise addition of neat trimethyl borate (175 ⁇ L, 1544 ⁇ mol) at the same temperature. The resulting mixture was stirred for 1 hour at ⁇ 78° C., warmed to 25° C., and stirred for an additional hour.
  • Butyl 4-bromo-3-(butyloxy)benzoate (5.1). To a flask containing 4-bromo-3-hydroxybenzoic acid (available from Combi-Blocks Inc.) (2.40 g, 11.06 mmol) and cesium carbonate (8.287 g, 25.44 mmol) in DMF (40 mL), was added 1-bromobutane (available from Aldrich) (2.494 mL, 23.22 mmol), and the mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and then purified by combiflash (0 to 20% EtOAc/Hexanes) to provide 5.1 (2.4326 g, 66.81% yield).
  • 4-bromo-3-hydroxybenzoic acid available from Combi-Blocks Inc.
  • cesium carbonate 8.287 g, 25.44 mmol
  • Butyl 2-(butyloxy)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-carboxylate (5.2).
  • 2-fluoro-5-methoxyphenylboronic acid available from Aldrich
  • tetrakis(triphenylphosphine) palladium(0) (0.7897 g, 0.6834 mmol
  • cesium fluoride (0.8409 mL, 22.78 mmol
  • 5.1 (1.50 g, 4.556 mmol
  • the resulting racemate was resolved by chiral HPLC (Chiralcel OD column, 3% IPA/hexane, 220 nm) to afford 5.7 (0.14 g, 22.7 minutes) and 5.8 (0.14 g, 36.1 minutes) as pale yellow oils.
  • Methyl (2Z)-4,4,4-trifluoro-3-(3-(methyloxy)phenyl)-2-butenoate (6.1).
  • Methyl 3-tert-butyl-4-(trifluoromethylsulfonyloxy)benzoate (8.7).
  • methyl 3-tert-butyl-4-hydroxybenzoate available from Apin Chemical Ltd, United Kingdom
  • TEA 0.080 mL, 0.58 mmol
  • DMAP 0.0059 g, 0.048 mmol
  • triflic anhydride 0.097 mL, 0.58 mmol
  • Example 10 was synthesized from 8.5 and 8.10 using a method analogous to the method used to prepare compound 7.
  • Example 11 was synthesized from 8.5 and 5.4 using a method analogous to the method used to prepare compound 7. MS ESI (neg.) m/e: 491.2 (M ⁇ H) + .
  • a dry round bottom flask containing 8.7 (1.40 g, 4.1 mmol), 3-methoxyphenylboronic acid (available from Aldrich) (1.27 g, 8.34 mmol), tetrakis(triphenylphosphine)palladium (0.49 g, 0.42 mmol), and potassium carbonate (1.71 g, 12.36 mmol) was evacuated and backfilled three times with argon. Dry DMF (12.0 mL) was added via syringe under argon, and the mixture was then heated to 100° C.
  • Ethyl 3-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzoate (14.1) A mixture of ethyl 3-chloro-4-hydroxybenzoate (available from Aldrich) (5.00 g, 25.0 mmol), N-phenyltriflimide (9.30 g, 26.0 mmol) and TEA (4.2 mL, 30.0 mmol) in DCM (40 mL) with a catalytic amount of DMAP, was stirred at ambient temperature overnight. DCM (150 mL) was added, and the reaction mixture was washed with brine (30 ⁇ 3 mL), dried over MgSO 4 , and the solvent was removed under reduced pressure. The product 14.1 was used in the next step without further purification. MS ESI (pos.) m/e: 335.0 (M+Na) + .
  • Ethyl 2-chloro-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-carboxylate (14.2) A reaction mixture of ethyl 3-chloro-4-(trifluoromethylsulfonyloxy)benzoate 14.1 (3.00 g, 9.02 mmol), 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (1.84 g, 10.8 mmol), (t-4)-tetrakis(triphenylphosphine)palladium (0.521 g, 0.451 mmol) and potassium carbonate (2.49 g, 18.0 mmol) in DMF (20 mL), was purged with N 2 three times and then heated at 100° C.
  • the enantiomers were resolved by chiral HPLC (Chiralcel OD-H column, 3% IPA/hexane, 220 nm wavelength used to observe the compound peaks) to afford 15.3 (0.400 g, 16.0% yield from 8.1) (28 minutes) and 15.4 (0.400 g, 16.0% yield from 8.1) (45 minutes).
  • Example 31 was synthesized from 27.1 by a method analogous to that used to prepare compound 27.
  • ESI neg.
  • m/e 451.1 (M ⁇ H) + .
  • Example 32 was synthesized from 27.1 by a method analogous to that used to prepare compound 27.
  • ESI neg.
  • m/e 477.2 (M ⁇ H) + .
  • Methyl 3-(3-hydroxyphenyl)propanoate (commercially available from Aagile Labs Division of Tyger Scientific) (0.025 g, 0.14 mmol) was alkylated by reaction with compound 8.10 (0.043 g, 0.14 mmol) according to the method given in Example 1 to give compound 34.1 as a clear oil (0.052 g, 83% yield).
  • Compound 37.3 was synthesized using the alkylation and hydrolysis procedure of Example 13 above using compounds 37.1 and 37.2.
  • 3-(3-Hydroxyphenyl)propanoic acid is available from Alfa Aesar Avocado, and Lancaster).
  • 4-(Bromomethyl)-1-chloro-2-(trifluoromethoxy)benzene is available from Alfa Aesar, Lancaster, and Avocado.
  • MS ESI (neg.) m/e: 373 (M ⁇ H).
  • Methyl 2-(1,1-dimethylethyl)-3′-(ethyloxy)-1,1′-biphenyl-4-carboxylate (41.1).
  • a dry round bottom flask containing 8.7 (1.13 g, 3.31 mmol), 3-ethoxyphenylboronic acid (available from Aldrich) (1.10 g, 6.63 mmol), tetrakis(triphenylphosphine)palladium (0.39 g, 0.340 mmol), and potassium carbonate (1.41 g, 10.20 mmol) was evacuated and backfilled three times with argon. Dry DMF (10.000 mL) was then added via syringe under argon. The mixture was then heated at 80° C.
  • the resulting racemate was resolved by chiral HPLC (Chiralcel OD column, 3% IPA/hexane, 220 nm) to afford 5.7 (0.14 g, 22.7 minutes) and 5.8 (0.14 g, 36.1 minutes) as pale yellow oils.
  • a screw-cap vial was charged with 5.7 (0.010 g, 0.051 mmol), 8.10 (0.017 g, 0.057 mmol), cesium carbonate (0.025 g, 0.077 mmol), and DMF (1.0 mL). The mixture was stirred overnight at room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried (MgSO 4 ) and concentrated, and the residue was chromatographed on silica gel (0-15% EtOAc/hexane) to afford a colorless oil. The oil was dissolved in 2:1 THF/MeOH (1.5 mL), and 1 N LiOH (0.5 mL) was added.
  • a mixture of (E)-ethyl 3-(3-(benzyloxy)phenyl)-2-methylacrylate 62.B (0.93 g, 3.1 mmol) and palladium on charcoal (10%, 0.1 g) in EtOH (25.0 mL) was flushed with hydrogen three times.
  • the reaction mixture was stirred at room temperature for 2-3 hours.
  • the catalyst was filtered away, and the solvent was removed.
  • the residue, ethyl 3-(3-hydroxyphenyl)-2-methylpropanoate 62.C was used in the next step without further purification.

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